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Z-DNA underlies the target choice of Aire by facilitating promoter poising [BLISS]

ABSTRACT: We profiled DNA double-strand break (DSB) formation genome-wide in medullary thymic epithelial cells to investigate how DSBs regulate Aire's target choices

ORGANISM(S): Mus musculus

PROVIDER: GSE224552 | GEO | 2024/03/11

REPOSITORIES: GEO

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Z-DNA underlies the target choice of Aire by facilitating promoter poising [ChIPmentation]

Project description:We profiled NELF and Aire binding in medullary thymic epithelial cells using ChIPmentation to investigate the logic of Aire's target choices

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Z-DNA underlies the target choice of Aire by facilitating promoter poising [ATAC-seq]

Project description:We profiled chromatin accessibility of medullary thymic epithelial cells to investigate the logic of Aire's target choices

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Z-DNA underlies the target choice of Aire by facilitating promoter poising [ChIP-seq]

Project description:We profiled Pol II binding in medullary thymic epithelial cells using ChIP-seq to investigate the logic of Aire's target choices

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Z-DNA underlies the target choice of Aire by facilitating promoter poising [CUT&Tag]

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Z-DNA underlies the target choice of Aire by facilitating promoter poising [RNA-seq]

Project description:We profiled transcriptome of medullary thymic epithelial cells from mice of various treatments and genotypes to investigate the logic of Aire's target choices

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Z-DNA underlies the target choice of Aire by facilitating promoter poising [scRNA-Seq]

Project description:Aire is an unconventional transcription factor (TF) that enhances the expression of thousands of genes in medullary thymic epithelial cells (mTECs), which promotes clonal deletion or phenotypic diversion of self-reactive T cells. The biological logic of Aire’s target specificity remains largely unknown as, unlike many TFs, it does not bind to a particular DNA-sequence motif. We implemented two orthogonal approaches to investigate Aire’s cis-regulatory mechanisms: construction of a convolutional neural network and leveraging of natural genetic variation via analysis of F1-hybrid mice. Both approaches nominated Z-DNA and Nfe2•Maf as putative positive influences on Aire’s target choices. Genome-wide mapping studies revealed that Z-DNA-forming and Nfe2l2-binding motifs were positively associated with the inherent ability of a gene’s promoter to generate DNA double-strand breaks (DSBs), and promoters showing strong DSB generation were more likely to enter a poised state with accessible chromatin and already-assembled transcriptional machinery. Consequently, Aire preferentially targeted genes with poised promoters. We propose a model whereby Z-DNA anchors the Aire-mediated transcriptional program by enhancing DSB generation and promoter poising. Beyond resolving a long-standing mechanistic conundrum, these findings suggest previously unexplored routes of manipulating T-cell tolerance.

2024-03-11 | GSE253215 | GEO

Z-DNA underlies the target choice of Aire by facilitating promoter poising

Project description:This SuperSeries is composed of the SubSeries listed below.

2024-03-11 | GSE224557 | GEO

Analysis of Aire effects on individual mice of different genetic backgrounds

2008-07-22 | GSE8564 | GEO

Stability of Aire-upregulated and Aire-neutral transcripts in medullary thymic epithelial cells

Project description:Aire-upregulated transcripts exhibit higher stability than the transcripts neutral to Aire's action in mTEChi

2020-05-05 | GSE140815 | GEO

Transcription profiling of mouse ire-deficient and wild-type littermate thymic medullary epithelial cells

Project description:We compared gene expression profiles of aire-deficient and wild-type littermate thymic medullary epithelial cells. This was done in order to determine whether Aire's effects differed among strains, and also among individuals of the same strain. Experiment Overall Design: Individual thymi were digested with collagenase, dispase and DNAse, and meduallary epithelial cells with the phenotype CD45-G8.8+Ly51intMHCclasssIIhi were isolated by FACS.

2008-10-18 | E-GEOD-8564 | biostudies-arrayexpress

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